Paclitaxel by the extract of the bark of the Pacific yew or docetaxel by the extract of the needle leave of the European yew are useful the anticancer agents and it is named generally with a taxane-based anticancer agent. The action mechanism binds to the microtubule and brings microtubular polymerization promotion, stabilization, and it is thought that it inhibits cell division. These taxane-based anticancer agents are used for cancer treatment widely, and the high effectiveness for many cancer tumors such as non-small cell lung cancer, breast cancer etc. have been already confirmed. However, as toxic (a side effect) of the taxane-based anticancer agent, leucopenia, neutropenia, peripheral neuropathy, nausea vomiting are reported, and there is usually individual difference of 5-10 times with the drug blood concentration of the taxane-based anticancer agent again, and the serious toxic appearance with the rise in blood paclitaxel density is reported to the observed case.
There is also an issue of bias due to individual differences in pharmacokinetics. It is shown paclitaxel is a substrate of P-glycoprotein (MDR1/ABCB1) which is one of the transporter drugs, and has been reported that paclitaxel also are metabolized by CYP2C8, CYP3A4 primarily receive. On the other hand, docetaxel metabolism is by CYP3A4. Therefore, there is a possibility that caused by genetic polymorphisms of drug metabolizing enzymes and drug transporters of these individual differences in pharmacokinetics.
In addition, it is also seen the relatively high incidence of allergic side-effects in its additive and it is estimated many allergic side-effects that these drugs cause. Supramolecular complex by taxane anticancer agent of the present invention may have a substrate selectivity to reach a solution to these as artificial enzymes.
Concepts, as long-lasting effect by having gradually released from the drug formulation, proposed in 1968 by Argentina of the United States company (now Johnson & Johnson), are a drug delivery systems that is (DDS). Been studied until today, the use of anticancer drugs have been actively studied in particular.
The reason for this is that the expansion of the various benefits of convenience such as drug suppression of side-effects of powerful anti-cancer agents and the enhancement of drug efficacy exist by DDS. For example, the anticancer drug paclitaxel (Taxol) has been using what was dissolved in anhydrous ethanol and Cremophor EL the like for non-water soluble.
Solubilization of Taxol, by immobilized on the L-glutamic acid and by DDS such as albumin and dextrin, are known. In a drug delivery system (DDS), the diameter of a particle is enlarged by the balance of both water solubility and lipo-solubility or the molecular weight etc., thus the EPR effect and the RES control effect become possible. By the EPR effect, a new blood vessel of the tumor is penetrated by particle of size 10-200 nm, and the medicine piles up the tumor tissue. Particles of not less than 400 nm as a foreign substance are eliminated by phagocyte action by the Kupffer cell of liver, or the cell of the macrophage system of the adrenal gland in RES control. Since it is decomposed by drug metabolism in liver, a thing of 5 nm or less is excreted by filtration by the glomerulus of the kidney.
Thus, it is possible to maintain concentration of drug in the living body by using the optimal diameter of a particle for a long period of time.
Such a method that improves the convenience of the drug is called as pro-drugging, but there are problems whether there is possibility of the autoclave sterilization in DDS for the safety. A positive electric charge in DDS for the cancer cell surface of the negative electrostatic charge is needed so that it is busy in endocytosis in a cancer cell more efficiently.
On the other hand, it was produced latex polymerization products as immunoassay materials conventionally, but all most are emulsion-polymerized in solution of surfactant, and a thing of soap-less not to exist of the surfactant is expected. This is because an existing surfactant influences the action as the latex diagnostic agent in a water solution.
Therefore, the present invention provides a novel graft-copolymer that is composed of a cationic derivative of a water-soluble linear polymer and an olefin compound monomer.
The present invention also provides a method of graft-polymerizing an olefin compound monomer onto a cationic derivative of a water-soluble linear polymer having a hydroxyl group in water using ceric ammonium nitrate to obtain a stable and soapless latex of the graft-copolymer.
This is used for antibody adsorption latex as diagnostic agent. This technique to produce latex of soap-less is thought important to form the supramolecular compound which might have substrate selectivity as an artificial enzyme. Thus, I could produce the latex polymerization products which were useful as drug delivery (DDS) materials.
The invention of U.S. Pat. No. 4,816,540 provides a novel graft-copolymer that is composed of a cationic derivative of a water-soluble linear polymer and an olefin compound monomer.
The invention described in U.S. Pat. No. 4,816,540 also provides a method of graft-polymerizing an olefin compound monomer onto a cationic derivative of a water-soluble linear polymer in water using ceric ammonium nitrate to obtain a stable and soap-less latex of the graft-copolymer.
Namely, the obtained latex sensitized with an antibody or an antigen is agglutinated using antigen or antibody, and it can be confirmed rapidly whether the antigen or the antibody is present. The latex used for the L.A. (Latex Agglutination) test is typically a pure, stable and soap-less substance and is also very effective as a non-viral gene delivery vector.
It is shown in U.S. Pat. No. 3,989,656 that a dextran-alkyl methacrylate graft composition is obtained by polymerizing an olefin compound monomer onto a water-soluble linear polymer, such as dextran, in water using ceric ammonium nitrate.
The present invention provides a novel graft-copolymer for drug delivery system (DDS) that is composed of a cationic derivative of a water-soluble linear polymer and an olefin compound monomer.
The present invention also provides a method of graft-polymerizing an olefin compound monomer onto a cationic derivative of a water-soluble linear polymer in water using ceric ammonium nitrate to obtain a stable and soap-less latex of the graft-copolymer, which is very effective as drug delivery system (DDS).